CN108883056A - For treating preparation, manufacturing method and the purposes of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue - Google Patents
For treating preparation, manufacturing method and the purposes of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue Download PDFInfo
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Abstract
The invention belongs to pharmaceutical fields, and are related to the external preparation of the extracellular matrix element for treating periphery joint, joint of vertebral column and/or connective tissue.Preparation claimed provide active pharmaceutical ingredient, particularly glucosamine sulfate or other glucosamine salts and added ingredient to impacted joint excellent (compared with existing analog) transdermal delivery.It also proposed the method and its therapeutical uses for producing the preparation.The effect of confirming proposed preparation by clinical test results.
Description
Technical field
The invention belongs to pharmaceutical fields.More specifically, its be related to for treat periphery joint (peripheral joint),
The surface preparation of the disease of the extracellular matrix element of joint of vertebral column (spinal joint) and/or connective tissue.
Background technique
Aminoglucose (2-amino-2-deoxy-D-Glucose), and especially glucosamine sulfate potassium chloride are endogenous sugar
The specific substrate and stimulant of amine glycan synthesis.It belongs to aminosugars and is glycosaminoglycan and further proteoglycans
Common precursor and construction unit (building block), and then become organism connective tissue (fascia, ligament, tendon,
Cartilage, joint, joint capsule and interverbebral disc) extracellular matrix ingredient.
Aminoglucose promotes the recovery of the cartilage surface of periphery joint and joint of vertebral column (including interverbebral disc), and prevents it from invading
Erosion.It also restores the bone tissue corroded below cartilage during joint disease advanced stage, increases the elasticity and rebound of cartilaginous tissue
Property and its to the resistance of mechanical stress, increase joint motion amplitude, improving synovia quality simultaneously improves microcirculation, improves joint tissue
Tropism and reduce oedema.
In addition, aminoglucose has anti-inflammatory and analgesic properties.Which reduce to non-steroidal anti-inflammatory drugs (nonsteroidal
Anti-inflammatory drug, NSAID) demand, allow reduce NSAID dosage or completely eliminate NSAID treatment.It presses down
The generation of the enzyme (clostridiopetidase A and phosphatidase) of the formation and destruction cartilaginous tissue of superoxide radical processed.
Aminoglucose has proved to be effective Chondroprotective agents in the prevention and treatment of bone and connective tissue metabolism disorder
(chondroprotector), especially in collagen and cartilage matrix, the bone and connective tissue metabolism disorder cause inflammatory
Change [1] with degeneration.(it is the specific substrate and structure list of glycosaminoglycan and proteoglycans in synovia to endogenous glucosamine
Member) concentration have a great impact to the development of degenerative disease and process.In the case where lacking endogenous glucosamine, glucose
Amine preparation supplements the aminoglucose in blood plasma and synovia, even reverses cartilage erosion to slow down.
Aminoglucose preparation is widely shown as containing glucosamine hydrochloride or the oral of glucosamine sulfate, injection and external preparation
Type, it is intended to which the single dose as 100mg to 1500mg is applied.
Preparation based on aminoglucose usually includes added ingredient dimethyl sulfide (DMS；Its another entitled mesyl first
Alkane (MSM)) and ascorbic acid, there is positive therapeutic effect to organism.More specifically, DMS has analgesia and anti-inflammatory work
With.In addition, it promotes the inactivation of hydroxyl radical free radical, improves the metabolic process of inflammation part and slow down the injury in peripheral neurons
Sexual drive.The blood vessel function of DMS antagonizing histamine, bradykinin and prostaglandin E1.
Ascorbic acid has significant anti-oxidant and antiplatelet characteristic, inhibits prostaglandin and inflammation and allergy
Other media generation, and participate in oxidation-reduction process, glycometabolism, blood clotting and the adjusting of regeneration.
Prior art discloses the medicament for treating joint disease, it includes glucosamine salt, DMS, ointment bases and non-
(2259204 C1 of patent RU, authorizes steroidal anti-inflammatory medicine on August 27th, 2005；007597 B1 of patent EA, December 29 in 2006
Day authorization).
Prior art discloses the medicaments for treating joint disease, and it includes include in acceptable ointment bases
Glucosamine salt, chondroitin sulfate salt and DMS (2271812 C1 of patent RU of authorization on March 20th, 2006).
Prior art discloses the medicaments for nursing periphery joint and backbone, and it includes chondroitin sulfates, sulfuric acid glucose
The mixture (the patent RU 2376011 of authorization on December 20th, 2009) of amine, acetylglucosamine and several ointment bases variants.
Prior art discloses the pharmaceutical composition for treating joint disease, it includes chondroitin sulfate, glucosamine salt,
MSM, Troxerutin, n-methyl-2-pyrrolidone and ointment bases (the patent RU 2408380 of authorization on January 10th, 2011).
Prior art discloses the compositions for treating joint and myalgia, by capsaicine class
(capsaicinoid), aminoglucose or its salt and ointment bases composition (on 2 10th, 2004 authorization patent US 6,689,
399)。
Prior art discloses the compositions for treating rheumatoid arthritis, and it includes in the feelings that analgestic is not present
The chondroitin sulfate of therapeutically effective amount, N- acetyl group d-glucosamine and the hyaluronic acid (patent that on January 3rd, 2008 announces under condition
Apply for US20080003258).
Prior art discloses transdermal arthralgia therapeutic combinations, and it includes 0.1% to 15% glucosamine sulfate chlorine
Change sodium and by selected from the transdermal composition of one or more of material compositions of the following group：Cetanol, stearyl alcohol, stearic acid, list
Tristerin, isopropyl myristate, lecithin, butylated hydroxytoluene, dimethicone, urea, potassium sorbate, hydrogen-oxygen
Change sodium, stearic acid polyoxyl 40 ester, EDETATE SODIUM and water (the patent application US20080102107 that on May 1st, 2008 announces).
However, all existing preparations based on aminoglucose all have disadvantage, which reduce use theirs in practice
Benefit.The reason of limiting the use of oral aminoglucose preparation in practice is to need orally to apply using high glucose amine concentration and for a long time
To provide required bioavilability, this may cause the significant stimulation of gastrointestinal tract and associated adverse side effect.
Existing exterior-applied formulation (cream, ointment, emulsion, gelling agent) comprising chondroitin and aminoglucose does not have logical
It crosses skin and active constituent and excipient ingredients is delivered to the effective mechanism of the synovial membrane around involved area by tissue.Therefore,
Although chondroitin and aminoglucose have potential efficient, the therapeutic effect of classical surfactant is much smaller than oral form.
There is provided the injection aminoglucose preparation of maximum bioavilability, (it is not for institute by distinctive method of administration
Have patient acceptable) and the limitation that needs to have trained health care professional to apply them.
All preparations listed above for transdermal delivery, which lack, is used for pharmaceutically active agents, especially for aminoglucose and
The transdermal carrier of the physical structure of its salt.(its molecular weight is in 179.2 (aminoglucoses) and 456.4 (sulfuric acid glucose for mentioned component
Amine) between) cause to deliver relatively small number of activating agent across skin.The excipient for improving percutaneous permeability is introduced into preparation
(for example, DMS) has only been slightly increased the bioavilability of said medicine activating agent.It shall also be noted that being most often claimed as promoting
The DMS for the ingredient that percutaneous permeability improves may have adverse effect, this leads to many contraindications.For example, in serious cardiovascular
Insufficiency, atherosclerosis, kidney or hepatopathy, stroke, gestation, stupor, angina pectoris, breast-feeding, glaucoma and cataract
In the case where, DMS avoids use.DMS can increase the adverse effect of other drugs.According to limitation, 9 years old children below and old
Nian Renying uses DMS with caution.
Patent application US20050232980 (on October 20th, 2005 is open) is disclosed for transdermal delivery aminoglucose and sulphur
The composition of the suspended form of aching and limp ossein, it includes 0.01% to 20% aminoglucoses；0.01% to 20% sulfuric acid is soft
Ossein；0.01% to 10% camphor；0.01% menthol；0.01% to 20% anti-inflammatory agent；And lecithin is organic solidifying
Glue, MSM, benzyl alcohol, benzoic acid, or combinations thereof form transdermal carrier (by individually or with other mentioned chemical components
Mixed instant lecithin oranogel is mixed with said medicine activity and auxiliary element).The lecithin oranogel
Micella has the ability for penetrating readily through skin having been found, and theoretically they can influence positively discussed drug
The bioavilability of active constituent.However, lecithin oranogel is present in three compositions system, the three compositions system is in phase
When in organic comprising lecithin, nonpolarity in a few tenths of and the weight percent of a few percent very narrow water concentration range
Solvent and water [3].Therefore, lecithin oranogel transport pharmaceutically a large amount of water soluble ingredient (such as aminoglucose and its salt
Ability) it is very limited.
Therefore, it is necessary to provide the more effective of active pharmaceutical ingredient and auxiliary element to impacted joint area transdermal to pass
The surfactant sent.
Summary of the invention
It is being proposed according to the present invention for treating the extracellular matrix of periphery joint, joint of vertebral column and/or connective tissue
In the preparation of element, use active pharmaceutical ingredient and auxiliary element transdermal delivery to the completely new approach-organized namely based on glue
The transdermal delivery system of beam and/or liposome structure it includes the aggregation at least containing following component and precipitates stable dispersion
System：
60% to 80% water by weight,
1.0% to 6.0% glycerol by weight,
0.7% to 4% butanediol by weight,
At most 12.1% C8 fatty alcohol by weight,
At most 3.5% C16 fatty alcohol by weight,
At most 4.2% C21 fatty alcohol by weight,
The ester of at most 2.0% C15-C17 fatty acid by weight,
At most 1.4% polysiloxanes by weight,
The C2 polyethylene glycol of at most 1.4 weight % by weight,
The C20 polyethylene glycol of at most 0.98 weight % by weight.
It is provided by least one set of or two groups of different structure compositions in terms of hydrodynamic diameter/size dispersion
Excellent transdermal delivery, wherein first group of ruler by activity and auxiliary element comprising being surrounded by lipid layer/associating with lipid layer
Very little micelle nano capsule composition for 0.1nm to 100nm and second group comprising having a size of 200nm to 8000nm micella and/or
Liposome structure.
The delivery system proposed with provide suitable of intramuscular injection and the high number that is provided than tablet or conventional ointment
Efficiency again provides aminoglucose and is delivered to target cell.In addition, in terms of anaesthetizing efficiency, preparation according to the present invention with it is commercially available
Non-steroidal anti-inflammatory drugs (NSAID) is identical horizontal or even preferably works than commercially available non-steroidal anti-inflammatory drugs (NSAID).?
The recovery of anesthesia efficiency and the activity in impacted joint and the required dosage aspect for reducing or eliminating NSAID, according to this hair
Bright preparation capable of permeating skin is equivalent to or the known medicament based on aminoglucose even better than for injection.
Surface applied activating agent according to the present invention prevents gastrointestinal enzyme to the degradation of active component and provides significant
Bigger therapeutic effect.
The preparation proposed combines two principles of confrontation osteoarthritis：Quick anti-inflammatory and anaesthetic effect；And by shadow
That rings tissue stablizes the reinforcing restored with cartilage, it is characterised in that effect after extended treatment.In addition, what is proposed is used to treat
The preparation of the extracellular matrix element in periphery joint, joint of vertebral column and/or connective tissue be during long-time service it is safe and
And seldom there is (if any) side effect.
Technical result of the invention is by significantly improving the pharmaceutical activity in blood plasma and synovia around affected area
The bioavilability of ingredient and auxiliary element is improved for treating periphery joint, joint of vertebral column and/or the cell of connective tissue
The pharmacological effect of the surfactant of epimatrix element.
Compared with existing preparation, due to by active pharmaceutical ingredient and excipient more effectively transdermal delivery to impacted
Joint, especially transdermal delivery glucosamine sulfate and other glucosamine salts, therefore the pharmaceutical preparation proposed substantially has more
Apparent treatment and anaesthetic effect.
Detailed description of the invention
Micella/liposome quantity (relative volume) presses the distribution of size in the sample of Fig. 1 preparation A.
Glucose amine concentration (μ g/mL) after Fig. 2 applies preparation A on the skin through shaving of animal, in rat plasma
The curve of (hour) at any time.
Total WOMAC during treating in Fig. 3 .2 group at any time scores (VAS).
Total WOMAC insufficiency during treating in Fig. 4 .2 group at any time scores (VAS).
Average NSAID (brufen) demand weekly during being treated in Fig. 5 .2 group.
Specific embodiment
The statement " % is by weight " of the amount for expression composition used throughout the specification means mentioned system
The percentage of the total weight of the weight and preparation of the ingredient in agent.
According to the present invention, for treating the system of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue
Agent is utilized polar medicine active constituent (especially aminoglucose) and excipient (such as DMS and/or ascorbic acid) transdermal delivery
The completely new approach of the microcapillary vascular circulation of corium and tissue around to impacted organ.More specifically, in addition to a kind of or
Except more kinds of active pharmaceutical ingredients, disclosed preparation also includes based on micella and liposome structure for transdermal delivery system
It unites and includes at least aggregation containing following component and the stable dispersion of precipitating：
60% to 80% water by weight,
1.0% to 6.0% glycerol by weight,
0.7% to 4% butanediol by weight,
At most 12.1% C8 fatty alcohol by weight,
At most 3.5% C16 fatty alcohol by weight,
At most 4.2% C21 fatty alcohol by weight,
The ester of at most 2.0% C15-C17 fatty acid by weight,
At most 1.4% polysiloxanes by weight,
At most 1.4% C2 polyethylene glycol by weight,
At most 0.98% C20 polyethylene glycol by weight.
The micella and liposome structure dispersed in the formulation can form at least two in terms of hydrodynamic diameter/size
Different groups, wherein it is bent to be similar to the Gauss with maximum value for the distribution of the quantity (relative volume) of structure and its characteristic size
Line.
More specifically, first group of the structure by the micella having a size of 0.1nm to 100nm, especially 15nm to 80nm
Nanocapsule composition, the wherein at least hydrodynamic diameter of 90% structure/having a size of 15nm to 100nm, and amounts of particles (phase
To volume) maximum distribution be 25nm to 50nm；The artificial lipid-coated that each micella is similar to keratinocyte film is surrounded
It and include that active constituent and excipient/and active constituent and excipient associate.
Second group by micella and/or liposome structure having a size of 200nm to 8000nm, especially 500nm to 7000nm
Hydrodynamic diameter/size of composition, wherein at least 90% structure can be 500nm to 7000nm, and amounts of particles is (opposite
Volume) maximum distribution can be 1500nm to 5000nm；This group of structure also include active constituent and excipient/with active constituent and
Excipient association.
Due to their specific composition and size, the nanocapsule of first group of structure can easily go in space between cells
Into without making histocyte deformation or damage histocyte.When by preparation massage into skin, micella is with effective and harmless
Mode passes through the space between cells of pore and dermal cell and microcapillary bed blood vessel enters blood flow.The artificial biological film of micella exists
It degrades when contacting blood plasma and discharges aminoglucose and excipient, from the synovia that blood flow is diffused into impacted joint, or first
Into in the tissue of impacted periarticular, subsequently into impacted joint itself.
When by preparation massage into skin, belongs to second group of larger structure and partially passed through in effective and harmless mode
Space between cells, but pore and corium channel are passed principally through, and aminoglucose and auxiliary element are discharged into microcapillary bed blood vessel
In, it is diffused into blood flow, subsequently into the synovia in impacted joint, or initially enters the tissue of impacted periarticular
In, subsequently into impacted joint itself.
As indicated in the research most preferably formed for being intended to determine disclosed preparation, list exactly as indicated on
Ingredient forms micella and liposome structure with the relative quantity indicated, provides its Thief zone ability and aggregation and settling stability,
The structure provides the excellent bioavilability and drug of active pharmaceutical ingredient at least 3 years time in turn
Storage stability.
In addition, by the manufacturing method for implementing claimed preparation described herein, the group of indicated dispersion
At providing the structure, especially micella and/or liposome.In addition, the packet only indicated in the description of preparation and manufacturing method
The amount for the ingredient being contained in dispersion provides the aggregation and settling stability and its Thief zone ability of proposed preparation
Combination, condition is to follow production technology described herein.
According to the present invention, the studies above shows that above-mentioned transdermal delivery system can be used for delivering for example any glucosamine salt,
Such as glucosamine hydrochloride, glucosamine sulfate, the glucosamine sulfate stable with sodium chloride or potassium chloride.It has been found, however, that making
The maximum bioavilability of aminoglucose in blood plasma and synovia is provided with glucosamine sulfate potassium chloride.
In one embodiment of the invention, the preparation proposed is for treating periphery joint, joint of vertebral column and/or knot
Form the extracellular matrix element of tissue.
In one embodiment, described " one or more of active pharmaceutical ingredients " is glucosamine salt, such as sulfuric acid Portugal
Osamine potassium chloride, wherein glucosamine salt, especially glucosamine sulfate potassium chloride are present in system with 4% to 14% amount by weight
In agent.In one embodiment, the range of the amount is by weight 7.0% to 9.5%.In another embodiment,
The amount is by weight 8.00%.
In another embodiment, one or more of active pharmaceutical ingredients are present in proposed preparation with effective quantity
In.In some embodiments of the present invention, disclosed preparation also may include other drugs active constituent, for example, heparin, ketone
Ibuprofen, lidocaine and other compounds.
Other than one or more of active pharmaceutical ingredients, the preparation proposed also includes at least following added ingredient：
60% to 80% water by weight,
1.0% to 6.0% glycerol by weight,
0.7% to 4% butanediol by weight,
At most 12.1% C8 fatty alcohol by weight,
At most 3.5% C16 fatty alcohol by weight,
At most 4.2% C21 fatty alcohol by weight,
The ester of at most 2.0% C15-C17 fatty acid by weight,
At most 1.4% polysiloxanes by weight,
At most 1.4% C2 polyethylene glycol by weight,
At most 0.98% C20 polyethylene glycol by weight.
In one embodiment, water is present in proposed preparation with 67% to 75% amount by weight；One
In a embodiment, water exists with 71.69% amount by weight.
In another embodiment, glycerol is present in preparation with 2.0% to 4.0% amount by weight；At one
In embodiment, glycerol exists with 3.0% amount by weight.
In another embodiment, butanediol is present in preparation with 1.0% to 3.0% amount by weight；One
In a embodiment, butanediol exists with 2.0% amount by weight.
In one embodiment, component C8 fatty alcohol is caprylic/capric triglyceride.In another embodiment,
C8 fatty alcohol (for example, caprylic/capric triglyceride) is present in preparation with 1.7% to 12.1% amount by weight, another
In one embodiment, C8 fatty alcohol is present in preparation with 3.0% to 7.0% amount by weight；And in another reality
It applies in scheme, C8 fatty alcohol is present in preparation with 5.0% amount by weight.
In one embodiment, C16 fatty alcohol is represented as cetanol.In another embodiment, C16 fatty alcohol
(for example, cetanol) is present in preparation with 0.3% to 3.5% amount by weight；In another embodiment, C16 rouge
Fat alcohol is present in preparation with 1.5% to 3.0% amount by weight；And in yet another embodiment, C16 fatty alcohol with
2.3% amount by weight is present in preparation.
In one embodiment of the invention, C21 fatty alcohol is represented as tristerin.In another embodiment party
In case, C21 fatty alcohol (for example, tristerin) is present in preparation with 1.0% to 4.2% amount by weight；Another
In one embodiment, C21 fatty alcohol is present in preparation with 3.0% to 4.0% amount by weight；And in another reality
It applies in scheme, C21 fatty alcohol is present in preparation with 3.8% amount by weight.
In one embodiment, the ester of C15-C17 fatty acid is represented as Cetyl octanoate.In another implementation
In scheme, the ester (for example, Cetyl octanoate) of C15-C17 fatty acid is present in 0.3% to 2.0% amount by weight
In preparation；In another embodiment, the ester of C15-C17 fatty acid is present in system with 0.7% to 1.3% amount by weight
In agent；And in yet another embodiment, the ester of C15-C17 fatty acid is present in preparation with 1.0% amount by weight.
In another embodiment, polysiloxanes is present in preparation with 0.3% to 1.4% amount by weight；?
In another embodiment, polysiloxanes is present in preparation with 0.3% to 1.0% amount by weight.In other implementation
In scheme, polysiloxanes is not present in preparation.
In another embodiment, C2 polyethylene glycol is stereth (steareth) -2.In another embodiment party
In case, C2 polyethylene glycol (for example, stereth -2) is present in preparation with 0.3% to 1.4% amount by weight；Another
In one embodiment, C2 polyethylene glycol is present in preparation with 0.7% to 1.3% amount by weight；And at another
In embodiment, C2 polyethylene glycol is present in preparation with 1.0% amount by weight.
In one embodiment of the invention, C20 polyethylene glycol is stereth -20.In another embodiment
In, C20 polyethylene glycol (for example, stereth -20) is present in preparation with 0.22% to 0.98% amount by weight；?
In another embodiment, C20 polyethylene glycol is present in preparation with 0.50% to 0.80% amount by weight；And again
In one embodiment, C20 polyethylene glycol is present in preparation with 0.66% amount by weight.
In one embodiment, one or more of added ingredients include 0.05% to 0.3% amount by weight
Aminopolycanboxylic acid's (acid belongs to ligand family and serves as the chelating agent for adjusting product stability), 0.12% to 1.0% with weight
The hydroxyethyl cellulose of the amount of meter and/or 0.005% to 0.05% silica gel by weight, serving as allows to adjust product
The rheology modifier of viscosity.
In another embodiment, one or more of added ingredients include 0.5% to 5% amount by weight
DMS。
In another embodiment, one or more of added ingredients include 0.05% to 0.3% amount by weight
Ascorbic acid.
In another embodiment, one or more of added ingredients include preservative and/or fragrance.
In another embodiment, one or more of added ingredients include 0.05% to 0.5% amount by weight
Capsaicine class, especially capsaicine, the camphor of 0.2% to 1.8% amount by weight, 0.00005% to 0.005% with weight
The ginger extract of the amount of meter, the peppermint oil and/or menthol of 0.02% to 1.5% amount by weight, is being applied to skin
There is " warming " or part anaesthetic effect, to assign patient comfort when skin.Particularly, 0.02% to 1.5% by weight
Amount the peppermint oil and/or menthol can be used as fragrance in preparation.
In another embodiment, one or more of added ingredients include standard antiseptic agent, especially 0.01% to
0.3% amount, in one embodiment, the methyl p-hydroxybenzoate of 0.2% amount by weight and/or 0.01% to
0.07% amount, in one embodiment, the methylisothiazolinone of 0.05% amount by weight.It " is free of to prepare
The white willow bark extract of 0.02% to 2.5% amount by weight and the mixture of propylene glycol can be used in the preparation of preservative "
(SAP) conventional preservative is replaced.
In another embodiment, one or more of added ingredients include 0.1% to 0.9% amount by weight
Buffer solution, especially three (methylol) aminomethane (HOCH2)3CNH2(hereinafter referred to as " Tris ").
In another embodiment, a kind of added ingredient includes the silica gel of 0.005% to 0.05% amount by weight,
Its ingredient that may act as the micella and liposome structure formed in dispersion.
In one embodiment, the preparation proposed has consisting of：
In order to prepare being mentioned for the extracellular matrix element for treating periphery joint, joint of vertebral column and/or connective tissue
Preparation out uses the production method included the following steps：
(i) it is added into the first blending tank：The high purity water of 60% to 80% amount by weight, then addition 1% to 6%
The butanediol of the glycerol of amount by weight and 0.7% to 4% amount by weight；It heats the mixture under continuous stirring
65 DEG C to 70 DEG C；
(ii) it is added into the second blending tank：One or more of C16 fat of 0.3% to 3.5% amount by weight
Alcohol, one or more of C21 fatty alcohols of 1% to 4.2% amount by weight, 1.7% to 12.1% amount by weight
One or more of C8 fatty alcohols, the ester of one or more of C15-C17 fatty acid of 0.3% to 2.0% amount by weight,
One or more of polysiloxanes of 0.3% to 1.4% amount by weight, one kind of 0.3% to 1.4% amount by weight
Or more the amount of polyethylene glycol C2 and 0.22% to 0.98% by weight one or more of polyethylene glycol C20；?
65 DEG C to 70 DEG C are heated the mixture under lasting stirring；
(iii) mixture of (ii) is added in the first blending tank under continuous stirring during 5 minutes, then makes to mix
It closes object to be cooled to 50 DEG C or lower and add one or more of pharmaceutically active agents under continuous stirring, then makes mixture cooling
Preservative and fragrance are added to 30 DEG C and under continuous stirring,
Thus the preparation of the extracellular matrix element for treating periphery joint, joint of vertebral column and/or connective tissue is produced.
In the method, one or more of pharmaceutically active agents include glucosamine salt, especially glucosamine sulfate or sulphur
Sour aminoglucose potassium chloride.
Equally in the method, can also before heating in step (i) into the first blending tank addition 0.05% to
The hydroxyethyl cellulose and/or 0.005% of the aminopolycanboxylic acid of 0.3% amount and/or 0.12% to 1.0% amount by weight
The said effect in description to the silica gel of 0.05% amount by weight, to generate the ingredient.
Equally in one embodiment, the method the step of in (iii), one or more of pharmaceutical activity are added
The amount of the DMS and/or 0.05% to 0.3% of 0.5% to 5% amount by weight by weight is then further added in agent
Ascorbic acid, the said effect in description to generate the ingredient.
Equally in another embodiment, the method the step of in (ii), by the mixture in the second blending tank
65 DEG C to 70 DEG C are heated to, the capsaicine class of 0.05% to 0.5% amount by weight, especially capsicum are then further added
Element, the said effect in description to generate the ingredient.
In another embodiment, the method the step of in (iii), add one or more of pharmaceutical activity at
Point, then add the camphor and/or 0.00005% to 0.005% amount by weight of 0.2% to 1.8% amount by weight
Ginger extract, the said effect in description to generate the ingredient.
In another embodiment, the method the step of in (iii), addition 0.01% to 0.3% is by weight
Amount methyl p-hydroxybenzoate and/or 0.01% to 0.05% amount by weight methylisothiazolinone as anti-corrosion
Agent, or 0.02% to 2.5% amount by weight of addition white willow bark extract and propylene glycol mixture (SAP) as the substitute of standard antiseptic agent.
Equally in some embodiments, the method the step of in (iii), one or more of pharmaceutical activity are added
Agent is simultaneously cooled to 30 DEG C, and then the peppermint oil and/or menthol of the amount of addition 0.02% to 1.5% by weight, the two are
Fragrance simultaneously assigns patient comfort.
Some embodiments of the method the step of in (i), after the water addition, added into the first blending tank
Three (methylol) aminomethanes of 0.1% to 0.9% amount by weight are as buffer solution, to keep making during long term storage
The pH value of agent.
In one embodiment, a kind for the treatment of method is disclosed, wherein by the preparation containing activating agent with length for extremely
The band that few 2 to 3 centimetres and diameter are at least 0.5 centimetre is administered on the skin at impacted joint or spine position and massages
Into skin until fully absorb, at least twice daily and at most 5 to 6 times daily, wherein the preparation is at least three periods
Between use, the process can be repeated if necessary, to realize treatment.In a preferred embodiment, the method is
The method for treating the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue.
For treating the preparation of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue proposed
With many beneficial medicinal properties.Main two are in these：1) the comparable articular cartilage provided with injection aminoglucose
Effective recovery with other extracellular matrix elements of connective tissue and 2) with commercially available NSAID quite and sometimes even
Apparent anaesthetic effect better than commercially available NSAID.
The beneficial medicinal property of preparation claimed further includes that effective prevention uses the wound or correlation after NSAID
The osteoarthritis and inflammatory disease in joint and ligament after disease stimulate intra-articular liquid to generate and improve its composition, Yi Jiwei
Hold the best viscosity of intra-articular liquid.
Pointed beneficial medicinal property provides improvement to the following indication for using proposed preparation：
The osteoarthritis of periphery joint and joint of vertebral column, osteochondrosis；
The inflammatory disease in joint, such as arthritis, including rheumatoid polyarthirtis；
The wound (dampen, rupture, sprain) of kinematic system element, periphery joint and joint of vertebral column；
Prevent injuries the osteoarthropathy and inflammatory disease of posterior joint and ligament；
Saving cortilage is from NSAID and hormone preparation (Indomethacin, orthofen, Diclofenac, prednisolone) to soft
The side effect of bone tissue；
Myalgia (myalgia (mialgia), myositis).
Embodiment
For the experimental study described in following embodiment 2-6, claimed invention has been prepared for it and has been covered
Exemplary formulation (hereinafter referred to as preparation A) (referring to embodiment 1).
The preparation of 1. preparation A of embodiment
The composition of preparation A is as follows：
In order to manufacture the preparation A of 100kg, following steps are taken.
(i) high purity water that the amount of 71.69kg is added into the first blending tank, then adds the glycerol and 2kg of the amount of 3.0kg
Amount butanediol；70 DEG C are heated the mixture under 60 to 70rpm lasting stirring.
(ii) then into the second blending tank add 2.3kg amount cetanol, the tristerin of the amount of 3.8kg,
The caprylic/capric triglyceride of the amount of 5.0kg, the Cetyl octanoate of the amount of 1.0kg, the poly dimethyl silicon of the amount of 1.0kg
Oxygen alkane, the stereth -20 of the amount of the stereth -2 and 0.66kg of the amount of 1.0kg；In 60 to 70rpm lasting stirring
Under heat the mixture to 70 DEG C.
(iii) mixture of (ii) is added to the first blending tank under 60 to 70rpm lasting stirring during 5 minutes
In, so that mixture is cooled to 50 DEG C or lower, and under 60 to 70rpm lasting stirring add 8.0kg amount sulfuric acid
Mixture is then cooled further to 30 DEG C, and adds 0.05kg under 60 to 70rpm lasting stirring by aminoglucose potassium chloride
The methylisothiazolinone of amount, 0.2kg amount methyl p-hydroxybenzoate and 0.3kg amount peppermint oil.
The structural research of 2. preparation A of embodiment
Use the Zetasizer Nano ZS device (Malvern, Britain) with lasing source 532nm's
Features described above (the structure of the structure formed in dispersion is determined at wavelength by dynamic light scattering (photon correlation spectroscopy)
Hydrodynamic diameter/size and its by hydrodynamic diameter/size quantity) (Fig. 1).
In Fig. 1, the report automatically generated shows relative volume that the particle in test sample occupies to particle size
Dependence.For example, the 17.9% of the test sample total volume that particle occupies correspond to hydrodynamic diameter be 15nm extremely
The particle of 80nm, and average hydrodynamic diameter is 43.62nm, and the 82.1% of test sample total volume is corresponded to stream
Body dynamics diameter is that 0.5 micron to 5 microns of particle occupies, and the average hydrodynamic diameter of the subset is
2005nm。
The research of aminoglucose bioavilability when using preparation A of embodiment 3.
In order to obtain the purpose about the objective information of aminoglucose bioavilability after dermal administration, have been carried out to big
The research of mouse.
Oral and intramuscular administration sulfuric acid glucose amine aqueous solution has been compared in Sprague-Dawley rat
With the relative bioavailability of the aminoglucose in the case where surface applied preparation A cream and the research of permeability.
Result presented below is obtained by the plasma glucose amine concentration in measurement rat.According to main research approach into
The research of 5 groups of rats of row (wherein every group in 9 rats).One group of surface applied preparation A cream, and another group of oral administration Portugal
Osamine solution and other three groups-its glucose amine concentration different by injection.
The analysis of pharmacokinetic curve based on the aminoglucose in rat plasma, it is determined that relative to intramuscular injection
The 4% glucosamine sulfate solution containing 400mg/kg dosage continues one week time 3 times a day, dynamic using 400mg/kg is provided
The preparation A cream of the dosage of object weight continues to lead within one week 61.6% bioavilability of aminoglucose 3 times a day.It is applying
Being delivered to the Mean Speed in blood plasma by animal skin with aminoglucose in 4 hours after cream is 26.9 μ g/cm2It is small
When.The relative quantity of aminoglucose during 4 hours time after single administration by dermal delivery into blood plasma is dosage
4.12%.
The comparative analysis of experimental data present in the experimental data and document of acquisition and based on this calculation shows that,
During the preparation A treatment such as applied in experiment, the mean concentration of the estimation of the aminoglucose in the synovia in inflammation joint is 0.7
μ g/ml to 1.5 μ g/ml is endogenous glucosamine concentration (the usually 0.02 μ g/ml to 0.07 μ g/ in person joint's synovia
M1 10 to 75 times of height).Described value is suitable with the value obtained by injection application aminoglucose, and is the aminoglucose of oral form
In the case of up to 2 times of height of value for obtaining.
The research of 4. preparation A stability of embodiment
The stability of test formulation A at any time under three kinds of different conditions：
(i) 25 ± 2 DEG C and 60 ± 5% relative humidity under be incubated for；
(ii) it is incubated at -15 DEG C, then thaws；
(iii) 40 ± 2 DEG C and 75 ± 5% relative humidity under be incubated for.
Preparation A is sealed in the container respectively containing 50g drug.For each in three kinds of conditions using three not
Same container.Many physics and chemical parameters are monitored at following time point within 3 years：
First Year：Every three months；
Second year：Every six months；
Third year：Once.
As a result it is shown in following.
No. 1 vessel fabrication date：On March 27th, 2012
Condition：25 ± 2 DEG C of temperature and 60 ± 5% relative humidity
No. 2 vessel fabrication dates：On March 28th, 2012
Condition：25 ± 2 DEG C of temperature and 60 ± 5% relative humidity
No. 3 vessel fabrication dates：On March 28th, 2012
Condition：25 ± 2 DEG C of temperature and 60 ± 5% relative humidity
No. 4 vessel fabrication dates：On March 27th, 2012
Condition：It is incubated at -15 DEG C, then thaws
No. 5 vessel fabrication dates：On March 28th, 2012
Condition：It is incubated at -15 DEG C, then thaws
No. 6 vessel fabrication dates：On March 28th, 2012
Condition：It is incubated at -15 DEG C, then thaws
No. 7 vessel fabrication dates：On March 27th, 2012
Condition：40 ± 2 DEG C and 75 ± 5% relative humidity under be incubated for
No. 8 vessel fabrication dates：On March 28th, 2012
Condition：40 ± 2 DEG C and 75 ± 5% relative humidity under be incubated for
No. 9 vessel fabrication dates：On March 28th, 2012
Condition：40 ± 2 DEG C and 75 ± 5% relative humidity under be incubated for
The result shows that product is still uniform cream and has at least 3 years although pH and viscosity reduce
Effect.
The example A processed of embodiment 5. andComparison
The effect of in order to confirm preparation claimed, has been carried out and compares randomized clinical trial to diagnose at 80
For test formulation A in the volunteer of knee joint I-III phase osteoarthropathy with (external-use gel,
NOVARTIS Consumer Health GmbH, Switzerland) efficiency, safety and tolerance.
In 80 patients, 68 are women, and 12 are males, and the age is between 44 years old to 80 years old.Due to screening and with
Machine, all patients meet inclusion criteria.
Patient is randomly divided into two groups：Experimental group (preparation A) and control group ( ).It is all
Patient completes research according to scheme.Two groups at age and gender, height and weight, systolic pressure and diastolic pressure, joint synthesis
Levy clinical score (Western and McMaster University arthritis index (the Western Ontario and
McMaster Universities Arthritis Index) or " WOMAC ", it is used for during walking and palpation using view
Feel analog scale (visual analog scale, VAS) pain Assessment is carried out in target joint) aspect do not have statistically
Difference.The statistically significant difference between two groups in terms of the radiology stage of gonarthrosis is not set up.Two groups are not disclosed yet
Between reliable difference in terms of most of lab index.Based on foregoing teachings, two groups can be considered as comparable.
The clinically significant deviation of blood pressure, pulse, electrocardiogram or lab index is not observed in the course of the research.?
In entire research, 11 slight adverse events are detected.Detect two adverse events related with the drug of application (in every group
One).Be both it is slight, do not need treatment and with restore terminate.In experimental group and control group respectively by 34 and
30 patients reach Primary Endpoint, correspond to " WOMAC pain " " reduce and be greater than 20% ".In addition, continuing after treatment is finished
Effect：In interview 4 respectively (the 56th day since treatment), 32 and 24 patients, still reach terminal.Knot between two groups
The significant difference of fruit not disclosed between experimental group and control group.Therefore, in terms of above-mentioned standard, the treatment of preparation A is imitated
Rate withTherapeutic efficiency statistically without difference (by carry out the research doctor infer).
According to both patient and clinician, 4 weeks after treatment is finished, the quantity of positive findings was statistically in experimental group
Significantly.In other words, the transdermal delivery system of aminoglucose is found and for mitigating pain
Quite, and in terms of the duration of therapeutic effect it is better than
6. preparation A of embodiment is compared with glucosamine sulfate injection form " Dona "
The effect of in order to further confirm the transdermal delivery system for aminoglucose of the invention, the present inventor is
Preparation A (medicinal external emulsifiable paste agent) has been carried out when treating kneed osteoarthritis in the patient for being diagnosed as gonarthrosis and has been used
In glucosamine sulfate (the injection ampoule of each 2ml, the sulfuric acid containing 200mg in 1ml of the injection form of intramuscular administration " Dona "
Aminoglucose potassium chloride) therapeutic efficiency comparative studies.
Before research, have evaluated 40 with confirmed knee joint osteoarthritis (gonarthrosis) (according to
R.Altman standard, 1995) and the patient with obvious pain syndrome.Patient age was from 48 years old to 75 years old (average age
56.7 ± 8.2 years old)；38 (95%) are women, and 2 (5%) are male.Year variation from 2 years to 15 of the duration of disease is (flat
The equal duration is 6.7 ± 2.9 years).It is classified according to Kellegren&Lawrence, in 30 (75%) patients, knee joint
The radiography grade of disease is confirmed as II, and in 10 (25%) patients, the radiography grade of gonarthrosis is true
It is set to III.In assessment, all 40 (100%) patients receive NSAID treatment.
Patient is divided into terms of major parameter two groups comparable (each 20 people).First group of surface receives preparation A, wherein will
The band that the length of cream is 2 to 3 centimetres and diameter is about 0.5 centimetre is applied to impacted joint area, three times per day,
Continue one month.Treating targeted joint is the joint that maximum pain is generated when studying and starting.Second group of patient is at one
Intramuscular receiving " Dona " three-times-weekly once a day during month.It is commented according to the dynamic of Articular Syndrome index in target knee joint
Estimate therapeutic efficiency.Assess following factor：Using pain intensity of the VAS in static and movement in joint, combined index and individually
Index dynamic：Pass through pain, constraint and insufficiency, the demand to NSAID (brufen) in the joint of WOMAC scoring.
Above-mentioned clinical parameter is assessed once a week when assessing first time and during one month.
As above-mentioned treatment as a result, in the case where the index that the severity for characterizing pain syndrome reduces, observe
To the most of dynamics for comparing WOMAC index.Over the course for the treatment of, observe and walk, go upstairs on a flat surface,
Significant (the p < 0.05) of the related pain of joint palpation reduce (referring to table 1, Fig. 1,2).The system of index between two groups is not observed
Significant difference on meter.However, observing the more significant (p of the sensation of pain as caused by palpation in the case where being treated with preparation A
=0.06) reduction, this perhaps can be applied to painful area by its direct surface to explain.
In this two groups, observe the improvement of reliable significant (the p < 0.05) of body movement, this show as at first group and
In second group 15 meters of patient's walking reduced respectively from 29.6 ± 12.18 seconds to 18.0 ± 6.1 seconds apart from the required time and from
It reduces to 18.25 ± 5.23 seconds (referring to table 1) within 30.7 ± 12.21 seconds.
In general, the reduction (57%) of total WOMAC index observed in preparation A patient when research closes to an end with
Referring to (being greater than 56%) observed in " Dona " group statistically without difference (referring to Fig. 3,4).
Over the course for the treatment of, every group show to the average demand of NSAID be substantially reduced greater than 15 times (referring to table 1, figure
5).In more detail, in the patient for receiving preparation A, 15 (75%) stoppings receive brufen, and the dosage of 5 (25%) subtracts
It is 7-10 times small.In the group of receiving " Dona ", after treatment 1 month, 16 (80%) patients no longer need brufen, and 4
The original doses of name patient reduce 3-5 times.
Articular Syndrome quantitative target of the table 1. in the case where preparation A (surface) and " Dona " (intramuscular)
The Main Conclusions of research described herein is activity of the proposed preparation in anaesthetic effect and impacted joint
Property recovery and reducing the average demand side weekly of NSAID is similar to over the course for the treatment of and in some cases
Better than the commercially available injection preparation based on glucosamine sulfate.
Cited document
1.Altman, R.D.Clinical Pharmacology2 (4), 359-371 (2009) [Russian]
2.Handbook on Drugs, Vidal：http：//www.vidal.ru/drugs/molecule/322.
3.Scartazzini R., Luisi P.L., Organogels from Lecithins//
J.Phys.Chem.92,829-833 (1988)
Claims (41)
1. preparation, it includes a effective amount of one or more of pharmaceutically active agents and at least following component：
60% to 80% water by weight,
1.0% to 6.0% glycerol by weight,
0.7% to 4% butanediol by weight,
At most 12.1% C8 fatty alcohol by weight,
At most 3.5% C16 fatty alcohol by weight,
At most 4.2% C21 fatty alcohol by weight,
The ester of at most 2.0% C15-C17 fatty acid by weight,
At most 1.4% polysiloxanes by weight,
At most 1.4% C2 polyethylene glycol by weight,
At most 0.98% C20 polyethylene glycol by weight.
2. preparation according to claim 1, wherein the preparation is for treating periphery joint, joint of vertebral column and/or connective
The extracellular matrix element of tissue.
3. preparation according to claim 1, wherein the ingredient in the preparation forms aggregation and precipitates stable dispersion
System, it includes micella and/or liposome structures.
4. preparation according to claim 3, wherein the structure forms at least one group, wherein at least 90% knot
The hydrodynamic diameter of structure/having a size of 15nm to 100nm, and by the maximum distribution of the amounts of particles of size be 25nm extremely
50nm。
5. preparation according to claim 3, wherein the structure forms at least two groups, wherein
In the first set, the hydrodynamic diameter of at least 90% structure/having a size of 15nm to 100nm, and press size
Amounts of particles maximum distribution be 25nm to 50nm, and
In the second set, the hydrodynamic diameter of at least 90% structure/having a size of 500nm to 7000nm, and press ruler
The maximum distribution of very little amounts of particles is 1500nm to 5000nm.
6. preparation according to claim 1, wherein the one or more active pharmaceutical ingredient is glucosamine salt.
7. preparation according to claim 6, wherein the glucosamine salt is glucosamine sulfate.
8. preparation according to claim 6, wherein the glucosamine salt is glucosamine sulfate potassium chloride.
9. preparation according to claim 8, wherein glucosamine sulfate potassium chloride exists with 4% to 14% amount by weight
In the preparation.
10. preparation according to claim 1 also includes the aminopolycanboxylic acid of 0.05% to 0.3% amount by weight.
11. preparation according to claim 1 also includes the hydroxy ethyl fiber of 0.12% to 1.0% amount by weight
Element.
12. preparation according to claim 1 also includes the dimethyl sulfide of 0.5% to 5% amount by weight
(DMS)。
13. preparation according to claim 1 also includes the ascorbic acid of 0.05% to 0.3% amount by weight.
14. preparation according to claim 1 also includes the capsaicine class of 0.05% to 0.5% amount by weight, special
It is not capsaicine.
15. preparation according to claim 1 also includes the camphor of 0.2% to 1.8% amount by weight.
16. preparation according to claim 1 also includes the silica gel of 0.005% to 0.05% amount by weight.
17. preparation according to claim 1 also includes the ginger extraction of 0.00005% to 0.005% amount by weight
Object.
18. preparation according to claim 1, wherein the preparation also includes 0.01% to 0.3% amount by weight
The methylisothiazolinone of methyl p-hydroxybenzoate and/or 0.01% to 0.05% amount by weight.
19. preparation according to claim 1, wherein the preparation also includes 0.02% to 2.5% amount by weight
White willow bark extract and propylene glycol mixture (SAP)。
20. preparation according to claim 1, wherein the preparation also includes 0.02% to 1.5% amount by weight
Fragrance, peppermint oil and/or menthol.
21. preparation according to claim 1 also includes the silica gel of 0.005% to 0.05% amount by weight.
22. preparation according to claim 1 also includes three (methylol) ammonia of 0.1% to 0.9% amount by weight
Methylmethane (HOCH2)3CNH2(Tris)。
23. preparation according to claim 1, it includes：
24. producing the side for treating the preparation of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue
Method comprising：
(i) high purity water of 60% to 80% amount by weight is added into the first blending tank, addition 1% to 6% is by weight
Amount glycerol；The butanediol of the amount of addition 0.7% to 4% by weight；65 DEG C are heated the mixture under continuous stirring
To 70 DEG C；
(ii) it is added into the second blending tank：One or more of C16 fatty alcohols of 0.3% to 3.5% amount by weight,
One or more of C21 fatty alcohols of 1% to 4.2% amount by weight, one kind of 1.7% to 12.1% amount by weight
Or more C8 fatty alcohol, the ester of one or more of C15-C17 fatty acid of 0.3% to 2.0% amount by weight,
One or more of polysiloxanes of 0.3% to 1.4% amount by weight, one kind of 0.3% to 1.4% amount by weight
Or more C2 polyethylene glycol and 0.22% to 0.98% amount by weight one or more of C20 polyethylene glycol；And
And 65 DEG C to 70 DEG C are heated the mixture under continuous stirring；
(iii) during 5 minutes, the mixture of (ii) is added in first blending tank under continuous stirring；Make
The mixture is cooled to 50 DEG C or lower；One or more of pharmaceutically active agents are added under continuous stirring；Make the mixing
Object is cooled to 30 DEG C；And preservative and fragrance are added under continuous stirring,
Thus the preparation of the extracellular matrix element for treating periphery joint, joint of vertebral column and/or connective tissue is produced.
25. according to the method for claim 24, wherein the one or more pharmaceutically active agents are glucosamine salts.
26. according to the method for claim 25, wherein the glucosamine salt is glucosamine sulfate.
27. according to the method for claim 25, wherein the glucosamine salt is glucosamine sulfate potassium chloride.
28. further including according to the method for claim 24, in step (i) first mixing described in the forward direction of the heating
The aminopolycanboxylic acid of the amount of addition 0.05% to 0.3% by weight in tank.
29. further including according to the method for claim 24, in step (i) first mixing described in the forward direction of the heating
The hydroxyethyl cellulose of the amount of addition 0.12% to 1.0% by weight in tank.
30. further including according to the method for claim 24, in step (iii) in the one or more of drugs of the addition
The DMS of 0.5% to 5% amount by weight is added after activating agent.
31. further including according to the method for claim 24, in step (iii) in the one or more of drugs of the addition
The ascorbic acid of 0.05% to 0.3% amount by weight is added after activating agent.
32. according to the method for claim 24, wherein in step (ii) after reaching 65 DEG C of temperature, to described second
The capsaicine of the amount of addition 0.05% to 0.5% by weight in blending tank.
33. according to the method for claim 24, wherein step (i) before heating, add into first blending tank
Add the silica gel of 0.005% to 0.05% amount by weight.
34. according to the method for claim 24, wherein step (ii) it is described be cooled to 50 DEG C after, to described second
The ginger extract of the amount of addition 0.00005% to 0.005% by weight in blending tank.
35. according to the method for claim 24, wherein adding 0.01% to 0.3% amount by weight in step (iii)
Methyl p-hydroxybenzoate and/or 0.01% to 0.05% amount by weight methylisothiazolinone.
36. according to the method for claim 24, wherein adding 0.02% to 2.5% amount by weight in step (iii)
White willow bark extract and propylene glycol mixture (SAP)。
37. according to the method for claim 24, wherein adding 0.02% to 1.5% amount by weight in step (iii)
Peppermint oil and/or menthol.
38. according to the method for claim 24, wherein in step (i) after adding water into first blending tank,
Three (methylol) aminomethanes of the amount of addition 0.1% to 0.9% by weight.
39. preparation, by producing according to the method for claim 24.
40. treatment method, wherein will according to claim 1 or preparation described in 39 is at least 2 to 3 centimetres with length and width is
At least 0.5 centimetre of band is administered on the skin at impacted joint or spine position, and massage into the skin until
Fully absorb, at least twice daily and at most 5 to 6 times daily, wherein the preparation daily using continue at least three weeks when
Between and be repeated up to realization treatment.
41. according to the method for claim 40, wherein the treatment method be treatment periphery joint, joint of vertebral column and/or
The method of the extracellular matrix element of connective tissue.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2015/000964 WO2017116273A1 (en) | 2015-12-30 | 2015-12-30 | Formulation for treatment of peripheral joints, spinal joints and/or extracellular matrix elements of connective tissue, method of manufacture and uses |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108883056A true CN108883056A (en) | 2018-11-23 |
Family
ID=56555697
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580085839.2A Pending CN108883056A (en) | 2015-12-30 | 2015-12-30 | For treating preparation, manufacturing method and the purposes of the extracellular matrix element of periphery joint, joint of vertebral column and/or connective tissue |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20190021995A1 (en) |
| EP (1) | EP3397241A1 (en) |
| JP (1) | JP2019501221A (en) |
| CN (1) | CN108883056A (en) |
| AU (1) | AU2015419323A1 (en) |
| EA (1) | EA201891380A1 (en) |
| WO (1) | WO2017116273A1 (en) |
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- 2015-12-30 WO PCT/RU2015/000964 patent/WO2017116273A1/en active Application Filing
- 2015-12-30 JP JP2018554305A patent/JP2019501221A/en active Pending
- 2015-12-30 EP EP15880672.9A patent/EP3397241A1/en not_active Withdrawn
- 2015-12-30 US US16/067,705 patent/US20190021995A1/en not_active Abandoned
- 2015-12-30 CN CN201580085839.2A patent/CN108883056A/en active Pending
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| CN103906524A (en) * | 2011-04-06 | 2014-07-02 | 玫琳凯有限公司 | Topical skin care formulations comprising plant extracts |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2015419323A1 (en) | 2018-07-26 |
| WO2017116273A1 (en) | 2017-07-06 |
| AU2015419323A8 (en) | 2018-12-20 |
| WO2017116273A8 (en) | 2018-08-30 |
| JP2019501221A (en) | 2019-01-17 |
| EP3397241A1 (en) | 2018-11-07 |
| EA201891380A1 (en) | 2018-12-28 |
| US20190021995A1 (en) | 2019-01-24 |
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